Renal failure is a condition that affects millions of people worldwide. It is characterized by shrinkage of the kidneys and progressive scarring within the kidneys, accompanied by excessive straining of the blood (hyperfiltration) by the remaining functional nephrons. The process of hyperfiltration often causes further reduction in kidney function that leads to a decrease in the ability of the kidneys to excrete wastes, concentrate urine, conserve electrolytes and maintain fluid balance. Yet, it is not until over 70% of the combined function of both kidneys is lost that most patients begin to experience symptoms of renal failure.
Renal failure can be divided into two main categories, namely, acute renal failure and chronic renal failure. Acute renal failure is characterized by a sudden decrease in kidney function which may occur following exposure to various therapeutic agents, radiotherapy or exposure to heavy metals and organic solvents. Chronic renal failure is more prevalent in elderly population and is often secondary to hypertension, diabetes, hyperlipidemia, and cardiovascular diseases. Renal failure can also result from cancer.
Untreated acute and chronic renal failure may progress into end stage renal disease wherein endogenous kidney function is irreversibly lost, a condition which renders the patient dependent upon dialysis or kidney transplantation. Approximately 90% of end stage renal disease is attributed to untreated chronic renal failure, whereas only 10% is attributed to acute renal failure.
The diagnosis of renal failure is usually performed by measuring the glomerular filtration rate (GFR) which provides an assessment of the filtering performance of the kidney nephrons. The two major markers used for determining GRF are urea and creatinine. In kidney failure, these markers which are normally excreted by the kidneys into the urine, are retained in the blood (reviewed by Carlson & Harrington in Diseases of The Kidney, 5th Ed., (Schrier & Gottschalk Eds.), Boston, Little Brown, 1993, p. 361; and Silkensen & Kasiske in The Kidney, 7th Ed., (Brenner Ed.), Philadelphia, 2003, p. 1107).
Although urea has been used as one of the first indicators for measuring GFR, recent studies have shown that urea is in effect a poor marker for determining GFR values. This is attributed to the many factors which influence plasma urea concentrations including, a dietary regimen with elevated protein intake, alcohol abuse and chronic liver disease. Other factors which influence urea levels in the blood are the state of hydration and tubular urea re-absorption. Additionally, some substances interfere with the accurate determination of plasma urea concentrations, including acetohexamide, allantoin, aminosalicylic acid, bilirubin, chloral hydrate, dextran, free hemoglobin, hydantoin derivatives, lipids (hyperlipidemia), sulfonamides, thiourea, and uric acid.
Creatinine is a metabolic product of creatine and phosphocreatine, which are both found almost exclusively in the muscle. Creatinine production is thus proportional to muscle mass and has little daily variability. Creatinine waste is transported through the bloodstream to the kidneys which filter out most of the creatinine. The level of creatinine in the urine and in the blood is thus indicative of kidney function. There are, however, several substances which affect the levels of creatinine including some commonly used medications (e.g. cimetidine, trimethoprim, pyrimethamine, and dapsone).
The hitherto known methods for diagnosing renal failure include physical examination wherein symptoms such as oral ulcers and pallor may indicate kidney disorder among other diseases and disorders. Blood tests and urinalysis are commonly used, wherein high levels of creatinine and blood urea nitrogen (BUN) are usually attributed to a decline in kidney filtration. As indicated previously, these tests tend to be highly inaccurate and may remain within the normal range even while 65%-75% of kidney fiinction is lost. Imaging techniques are also applied to detect changes in size, texture and position of the kidneys. These measurements are performed using ultrasound and are suitable for patients suffering from progressive renal failure.
Presently, renal biopsy remains the most definitive test to specifically diagnose chronic and acute renal failure. This method is invasive and thus includes the risk of bleeding among other possible complications. Furthermore, accurate interpretation of renal biopsy requires the expertise of a pathologist with extensive experience in analyzing biopsies.
Several markers have been re cently identified as being indicative of various kidney disorders, among which are β2-microglobulin, N-Acetyl-Glucosaminidase (NAG), Immunoglobulin G (IgG), transferrin, and interleukin-6. Particularly important biomarkers are secondary and tertiary amines, including dimethylamine and trimethylamine which were shown to be elevated in exhaled breath of end-stage renal disease patients (Simenhoffet et al., N. Eng. J. Med., 297, 132, 1977). U.S. Pat. No. 6,589,748 discloses a method of diagnosing early stages of renal diseases comprising separating all proteins in a urine sample and detecting a modified form of a protein in the sample indicative of an early stage of the renal disease. Proteins which can be used for this method are preferably albumin, globulin, euglobulin and pseudoglobulin. U.S. Pat. No. 7,138,229 provides a method for detecting kidney disease markers from a urine sample using reagents for the detection of a CXCR3 ligand or CCR-5 receptor ligand. Wang et al. (Appl. Phys. Lett., 91, 222101, 2007) teaches the use of AlGaN/GaN high electron mobility transistors functionalized with specific antibodies for the detection of a kidney injury disease biomarker (KIM-1) in the blood.
Electronic nose devices were shown to be applicable for the detection of renal dysfunction. Natale et al. (Physiol. Meas., 20, 377, 1999) discloses the use of quartz microbalance (QMB) sensors coated with different metallo-porphyrins for detecting traces of blood and quantitatively evaluating the pH and the specific weight of urine samples. Fend et al. (Biosens. & Bioelectro., 19, 1581, 2004) discloses the use of sensors of conducting polymers based on polyaniline for monitoring haemodialysis. The results were compared to traditional biochemistry analysis of urea, creatinine, carbon dioxide, phosphate and calcium phosphate products in the blood. The conducting polymer sensors along with principle component analysis and hierarchical cluster analysis provided discrimination of pre-dialysis blood from post-dialysis blood.
Breath analysis for the diagnosis of uremia using an electronic nose device was demonstrated by Lin et al. (Sens. & Actuat. B, 76, 177, 2001). A sensor module composed of six 12 MHz AT-cut quartz crystals array coated with probe peptides designed by simulating the olfactory receptor protein docking with target gas molecules in combination with discriminating analysis, were used. Breath analysis of normal subjects, patients with uremia, patients with chronic renal insufficiency (CRI) and patients with chronic renal failure (CRF) provided discrimination with a correct classification of 86.78%.
Voss et al. (Ann. Biomed. Engin., 33(5), 656, 2005) disclosed the application of an electronic nose system based on doped semiconductor metal oxide gas sensors for studying human body odor in patients with different stages of renal insufficiency. Principle component analysis (PCA) followed by quadratic discriminant analysis produced discrimination of all healthy subjects from renal patients and further discrimination of dialysis patients from patients with chronic renal failure with a correct classification of 95.2% for two principle odor components and 98.4% for three principle odor components.
There is an unmet need for diagnosing renal insufficiencies with adequate sensitivity and specificity in order to provide a large-scale screening technique for subjects at increased risk of developing renal dysfunction, feasible for clinical practice. Furthermore, there remains a challenge for the early detection of acute and chronic renal failure of various etiologies.